Alicyclic (secondary) amino alkyl benzoates



Patented Nov. 1, 1949 ALICYCLIC (SECONDARY) AMINO BENZOATES.

Amt

Arthur C. Cope, Belmont, Mas's.,' assignor to Sharp & Dohme,Incorporated, Philadelphia, Pa.,acorporation of Maryland No Drawing.Original application May 31, 1944,

Serial No. 538,201. Divided and this application December 19, 1946,Serial No. 717,317

4 Claims. (01. 260-477) O 0 o lhNHR in which R represents a hydrocarbonalicyclic group attached to the amino nitrogen and having a total ofless than eleven carbon atoms and selected from the unsubstituted andalkyl-substituted cyclopentyl groups, and R1 represents the divalentalkylene group, residue of the propanol or butanol, and has a total ofat least three f and less than five carbon atoms and with at least twoand less than four carbon atoms linked in sequence between the nitrogenand the oxygen.

Thus, it is seen that both the alkyl substituent on the amino group andthe amino group itself are secondary, and that the secondary amino groupis derived from ammonia by replacing one of its hydrogens by thehydrocarbon alicyclic substituent and a second hydrogen by the alkylenegroup. Accordingly, in this specification and in the claims theexpression alicyclic(secondary)- amino is used to describe thealicyolic-amino grouping on the propanoland butanol-amine portion of theester compounds of the invention and to show the amino group is alwayssecondary and that the alicyclic substituent on the amino group isalways secondary as one of its nuclear carbons is linked to thenitrogen.

The alicyclic substituent on the amino group of the alkylaminoalkanolportion of the ester compounds of the invention contains at least fiveand no more than ten carbon atoms and may be unsubstituted as merely thecyclopentyl radical or may be monoor poly-substituted as with otheralkyl groups such as the 3-ethylcyclopentyl radical and the like.

The esters of the invention are prepared by suitable reaction betweenbenzoic acid anhydride or a benzoyl halide such as benzoyl'chloride orbromide with the desired alicyclic(secondary)- amino-propanol or-butanol. In preparing the esters starting with an alkylaminoalkanolcontaining a non-tertiary alcohol group, the benzoyl ent on its aminogroup. An advantageous pro cedure for condensing the benzoyl compoundwith the salt of the aminoalkanol is to dissolve the aminoalkanol in aninert solvent such as a chlorinated lower paraffin hydrocarbon aschloroform or methylene chloride and the like and to convert it to itsaddition salt such as the hydrochloride by saturating the solution withdry hydrochloric acid gas, with cooling, and then to add to the solutionan equal molal quantity of the benzoyl halide as benzoyl chloridedissolved inan equal quantity of the same solvent, and heating thereaction mixture under reflux at to C., or higher, but preferably at thelower temperature range, then cooling the reaction mixture and removingthe solvent under vacuum, and if the free base is desired, then treatingthe reaction product suspended in water with sufficient suitable alkalias sodium carbonate monohydrate to liberate the free amino ester.

The inventionmay be illustrated by, but'no restricted to, the followingexamples: I

Example 1. 1 -cyclopentylamino-Z-propyl banzoate hydrochZorida-Asolution of 0.1 mol of 1- cyclopentylamino-2-propanol in 30 gramsof'chloroform was saturated with dry hydrogen chloride gas, withcooling. A solution of 14.0 grams (0.1 mol) of benzoyl chloride in 30grams of chloroform was added and the solution was heated in a bath at,50-55 C. for four days under a reflux condenser protected fromatmospheric moisture. Then the solvent was removed by vacuumdistillation while the mixture was warmed on a water bath; Benzene wasthen added to the syrupy residue and the reaction product crystallizedout after th'e'benzene was removed by vacuum distillation. Thecrystallized solid residue was washed with anhydrous ether to remove anyunreacted benzoyl chloride. The l-cyclopentylamino-Z- propyl benzoatehydrochloride obtained was purified by two recrystallizations fromabsolute alcohol; It melted at 151-152 C.

Example 2.2-oyclopentylamino-l-p-ropyl benzoate hydrochloride melting at165.5-166.5 C. was

obtained byreplacing the alkylaminoalkanol of Example 1 by the molalequivalent of 2 -cy clopentylamino-l propanol.

Included also as having similar local anesthetic use are othercyclopentyl(secondary)aminoalkyl benzoat'es obtained fromalkylaminoalkanols having a non-tertiary alcohol group. These'b'enzoatesembrace those having" no substituent, on

the cyclopentyl nucleus as well as those having a lower alkyl radicallinked to one or more of the cyclopentyl nuclear carbons. Preferably inthose having such hydrocarbon substituent on the cyclopentyl group, thetotal number of carbon atoms in the substituted cyclopentyl group isless than eleven. These benzoates are prepared by the same procedure asdisclosed in Example 1 by replacing the 1-cyclopentylamino-2-propanol ofExample 1 by the corresponding cyclopentyl- (secondary) aminoalkanol,for example, 2-cyclopentylamino-l-butanol, 2 cyclopentylamino 2- methyl1 propanol, 3-cyclopentylamino-1-propanol, and1-(3-ethylcyclopentyl)amino-2-propanol, to give additionalcyclopentyhsecondary) amino-alkyl benzoates, respectively as followsr Inpreparing the esters starting with an alkylaminoalkanol containing atertiary alcohol group, the desired alicyclicamlnoalkanol having thetertiary alcohol group and containing the desired alicyclic substituenton its amino group is reacted with a substantial excess such as a 50%excess of the benzoyl halide or benzoic acid anhydride to form thecorresponding benzamide, that isthe N-benzoyl derivative of the selectedalicyclicaminoalkanol, which amide is then rearranged to thecorresponding ester hydrochloride, for example, by boiling in absolutealcohol with an excess of concentrated hydrochloric acid. Such proceduremay be illustrated by, but not restricted to, the following example:

Example 3.1-cyclopentyZamino-2 methyl-2- propyl benzoatehydrochZoride.-0.15 mol of benzoyl chloride in 100 cc. of methylenechloride was added rapidly to a vigorously stirred suspension of 0.1 molof 1-cyclopenty1amino-2-methyl-2- propanol in 200 cc. of 5% aqueoussodium hydroxide. The mixture, vigorously mechanically stirred, washeated on a water bath so that the methylene chloride refluxed for onehour. The reaction mixture was cooled and separated into two layers. Theaqueous layer was extracted once with methylene chloride and theextract'was combined with the methylene chloride layer and thecombination was washed twice with water and concentrated under vacuum todryness.

The dry benzamide of 1-cyclopentylamino-2- methyl-Z-propanol wasrecrystallized once from etherv and pentane and melted at 90-91 C. Itwas then rearranged to its corresponding benzoate hydrochloride byboiling a solution of 0.05 mol of the benzamide in 250 cc. of absolutealcohol with a 60% molar excess of concentrated hydrochloric acid forlive minutes. Then the solution was cooled and vacuum distilled todryness. The residue was further dried by adding benzene andreconcentrating under vacuum, and then recrystallized from acetone. Thethusv purified 1'- cyclopentylamino 2 methyl-Z-propyl benzoatehydrochloride melted at 154155 C;

The esters of the invention are thus prepared from a wide variety ofalicyclicamino-alkanols selected from the -propanols and the -butanols,which alkanols then include a wide variety of such as the2-alicyclic(secondary)amino-l-alkanols, and 3 alicyclic(secondary) amino1-alkanols, and also 1-alicyclic(secondary)amino-2- alkanols, in all ofwhich the alkanol group is selected from the propanol and butanolgroups,

which alkanol groups may contain the alicyclicamino grouping as the solesubstituent or may contain additional substituents on the alkanolcarbons, such as an alkyl radical, preferably a lower alkyl radical, onthe 1-, 2- and 3-carbon atoms.

The various suitable alicyclic(secondary)amino-propanois and -butanolsadvantageously may be prepared by condensing a ketone with a primaryamino alcohol, With simultaneous or subsequent reduction, the mechanismof which is the formation of an intermediate alkylidene amino alcohol,or the formation of an intermediate oxazolidine or the formation of anintermediate mixture of both. Such advantageous procedure is describedin my copending application Serial No. 489,499, filed June 3, 1943 (nowabandoned), reference to which is made for details of such procedure.

While the various examples 1 through 3' show the preparation of thebenzoate hydrochloride, if the free base is desired instead, it isprepared by dissolving or suspending the hydrochloride in a small volumeof alcohol, diluting with water and treating with an excess over the soichiometric quantity of sodium carbonate. The liberated free base isextracted with benzene and recovered therefrom in known manner. If asalt of an acid other than hydrochloric acid is desired, then to asolution of the free base, for example, in benzene, there isadded thestoichiometric quantity of the particular acid of which the additionsalt is desired, and the solvent is then removed by evaporation, undervacuum if desired, and the desired. addition salt obtained bycrystallization.

The anesthetic compounds of the invention are the free amines, that is,the free bases. Ordinarily they are used in the form of addition salts,for example, as a hydrochloride, sulfate, sulfamate, tartrate, glycolateor other addition salt, as the free amines or bases are quite insolublein water. The selected salt should have sufficient solubility in waterto be completely soluble in the concentrations used, usually of theorder of 1% or less. The hydrochlorides and the glycolates are amongthose particularly therapeutically effective. The esters in which thealicyclic substituent on the amino group contains five carbon atoms inthe alicyclic nucleus and, if hydrocarbon substituted has less thaneleven carbon atoms, are particularly effective.

While these various individual illustrations of the benzoic acid estersof the invention have been separately named as a certain butyl benzoateor as a certain propylbenzoate, as exemplified in starting with 1-cyclopentylamino-Z-propyl benzoate. as in Example 1. and continuing from therethrough the disclosure ending with l-cyclopentylamino-2-methy1-2-propylbenzoate, insofar as nomenclature iscOncerned each of the variousindividual esters embraced in the. invention is either a-benzoic acidester of an alicyclic(secondary) -amino-propanol or of analicyclic(secondary) -amino-butano1.

This application is a division carved out of my copending applicationSerial No. 538,201, filed May 31, 1944 (now abandoned), which in turn isa continuation in-part of my copending-application Serial No. 505,039;filed-October 5, 1943, now

75 Patent NO; 2,442,721.

5 What is claimed is: 1. Alicyclic (secondary) amino-alkyl of thegeneral formula benzoates and their hydrochlorides, in which R1 is adivalent alkylene radical having a total of at least three and less thanfive carbon atoms with from two to three carbon atoms linked in sequencebetween the nitrogen and the oxygen, and in which R2 is selected fromthe cyclopentyl radical and the cyclopentyl radical substituted with oneor No references cited.

Certificate of Correction Patent No. 2,486,375 November 1, 1949 ARTHURO. COPE It is hereby certified that error appears in the printedspecification of the above numbered patent requiring correction asfollows:

Column 4, line 75, for the patent number 2,442,721, read 2,442,797;

and that the said Letters Patent should be read with this correctiontherein that the same may conform to the record of the case in thePatent Office.

Signed and sealed this 21st day of March, A. D. 1950.

THOMAS F. MURPHY,

Assistant Oommz'ssz'omr of Patents.

